Limonin derivatives and preparation methods and uses thereof

Abstract

The present invention provides a limonin derivative and a preparation method and use thereof. The limonin derivative has a structure shown in the following formula I. The limonin derivative of the present invention can inhibit the expression of TNF-α produced by RAW264.7 macrophages and primary mouse microglia caused by lipopolysaccharide, can block the excessive production of pro-inflammatory factors, and can be developed as a drug for treating inflammation.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemistry, and in particular to limonin derivatives and preparation methods and uses thereof. Background Art

[0002] Inflammation is a highly coordinated and complex basic pathological process that occurs when biological tissues and organisms are stimulated by certain stimuli (such as trauma, infection and other damaging factors). It is a common clinical symptom and plays a very important role in innate immunity by repairing damaged tissues, protecting the body and initiating healing mechanisms. Under normal circumstances, inflammation is beneficial and is an automatic defense response of the human body. However, if the inflammatory response is out of control or overexpressed, it will damage the body, such as attacks on the body's own tissues, inflammation in transparent tissues, etc. Inflammation is mainly divided into acute inflammation and chronic inflammation. Acute inflammation has an acute onset but a short duration. It is characterized by exudative lesions. The inflammatory cell infiltration is mainly granulocytes, followed by monocytes that can differentiate into macrophages or dendritic cells. The inflammatory response is accompanied by the degranulation and activation of local mast cells and macrophages, as well as the release of a variety of proinflammatory mediators, including bioactive amines (histamine and 5-hydroxytryptamine), cytokines (IL-1 and TNF-α) and chemokines. The resulting vasodilation and increased vascular permeability allow leukocytes and plasma to extravasate into the site of injury or infection. Neutrophils then move along the chemotactic gradient created by cytokines and components of the complement pathway (especially C5a). Recruited neutrophils will attempt to destroy inflammatory factors in order to ultimately resolve and heal inflammation. Chronic inflammation occurs when inflammatory factors cannot be removed during an acute response or if there is a problem with intracellular checkpoints, so it lasts for a long time and is often dominated by proliferative lesions, with inflammatory cell infiltration dominated by macrophages and lymphocytes. Unresolved chronic inflammation is a core component of a range of chronic diseases, including autoimmune and neurodegenerative diseases. For example, Alzheimer's disease (AD), acute ischemic stroke (AIS), Parkinson's disease (PD), and cardiovascular diseases are closely related to a variety of chronic diseases. They are the main immune cells of the central nervous system and play a vital role in maintaining the stability of the central nervous system and in the process of damage repair. Microglia-mediated inflammatory responses play a key role in the occurrence and development of diseases such as cerebral ischemia and neurodegenerative diseases. Lipopolysaccharide (LPS) can induce changes in the phenotype of microglia and release a series of inflammatory factors, such as TNF-α, NO, iNOS, PGE2, etc., causing inflammation and tissue damage. Inflammation-related diseases still pose a great threat to human health, and more targeted drugs are yet to be developed.

[0003] Limonin (hereinafter referred to as compound 1) is generally concentrated in the fruits of citrus plants, especially in seeds. The pure product is white, bitter, crystalline, and has certain anti-cancer and anti-viral effects and other beneficial biological activities. Summary of the invention

[0004] Based on this, it is necessary to provide a limonin derivative and a preparation method and use thereof, wherein the limonin derivative can block the excessive production of pro-inflammatory factors in the brain and provide a feasible treatment strategy for treating inflammation.

[0005] In a first aspect, the present invention provides a class of limonin derivatives or pharmaceutically acceptable salts thereof, wherein the limonin derivative has a structure shown in the following formula I:

[0006]

[0007] in, represents a single bond or a double bond, Indicates a single key or does not exist, Indicates that the configuration is α or β;

[0008] A, B, C, D, E and A' represent fused rings, respectively, wherein Rings A, D, and E can be in an open or closed state, and

[0009] in,

[0010] When ring A is in a closed ring state, R is an oxo group, and when ring A is in an open ring state, R

[0011] is hydroxyl group;

[0012] When the ring D is in a closed ring state, R' is an oxo group or a hydroxyl group, and when the ring D is in an open ring state, R' is a hydroxyl group;

[0013] When the ring E is in a closed ring state, R" is an ether group, and when the ring E is in an open ring state, R" is a hydroxyl group.

[0014] Among them, when rings A and D are in an open loop state, The "O" at one end is a hydroxyl group, and

[0015] R 1 Selected from H or acetyl.

[0016] In a specific embodiment, in Formula I, rings A, D and E are in a closed ring state, and the configuration of the hydroxyl group on ring B is α or β.

[0017] In a specific embodiment, in Formula I, rings A and D are in an open-ring state; ring E is in a closed-ring state, and the configuration of the hydroxyl group on ring B is α or β.

[0018] In a specific embodiment, in Formula I, ring A is in an open ring state; rings D and E are in a closed ring state, and the configuration of the hydroxyl group on ring B is α or β.

[0019] In a specific embodiment, in Formula I, rings A, D, and E are in an open-ring state; and the configuration of the hydroxyl group on ring B is α or β.

[0020] In a specific embodiment, in Formula I, rings A and E are in an open-ring state, ring D is in a closed-ring state, and the configuration of the hydroxyl group on ring B is α or β.

[0021] In a specific embodiment, the limonin derivative is selected from one of the following compounds:

[0022]

[0023] In a second aspect, the present invention provides a method for preparing the above limonin derivative, the method comprising the following steps: subjecting limonin to a reduction reaction in the presence of a reducing agent to generate the limonin derivative.

[0024] In a specific embodiment, in the reduction reaction, the reducing agent is selected from sodium cyanoborohydride, sodium borohydride or lithium aluminum hydride.

[0025] In a specific embodiment, when the reducing agent is sodium cyanoborohydride, compound 1a can be obtained.

[0026] When the reducing agent is sodium borohydride, compounds 1a, 1c-1g can be prepared respectively depending on the reaction time.

[0027] When the reducing agent is lithium aluminum hydride, compound 1h can be prepared.

[0028] In a third aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned limonin derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0029] In a specific embodiment, in the pharmaceutical composition, the mass percentage of the limonin derivative or the pharmaceutically acceptable salt thereof is 1 wt % to 96 wt %, preferably 10 wt % to 85 wt %.

[0030] In a specific embodiment, the pharmaceutically acceptable carrier includes one or more selected from sugar, starch, cellulose and its derivatives, gelatin, talc, solid lubricants, vegetable oils, polyols, emulsifiers, wetting agents, colorants, flavoring agents, stabilizers, antioxidants, preservatives and pyrogen-free water.

[0031] In a fourth aspect, the present invention provides use of the above limonin derivative or the above composition in the preparation of anti-inflammatory drugs.

[0032] In a fifth aspect, the present invention provides a method for treating inflammatory diseases, comprising administering a therapeutically effective amount of the above-mentioned limonin derivative, a pharmaceutically acceptable salt thereof, or a composition comprising the limonin derivative or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0033] Beneficial Effects

[0034] The limonin derivatives of the invention can inhibit the expression of TNF-α produced by RAW264.7 macrophages and primary mouse microglia cells induced by lipopolysaccharide (LPS), can block the excessive production of pro-inflammatory factors, and provide a feasible treatment strategy for treating inflammatory reactions. DETAILED DESCRIPTION

[0035] In order to facilitate the understanding of the present invention, the present invention will be described more comprehensively below, and preferred embodiments of the present invention are provided. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0037] Definitions and General Terms

[0038] Unless stated otherwise, the following terms used in the specification and claims have the following meanings.

[0039] The compounds of the present invention may exist in unsolvated forms as well as solvated forms containing pharmaceutically acceptable solvents (such as water, ethanol, etc.), that is, they include both solvated and unsolvated forms.

[0040] In the present invention, a substitutable site may be substituted with one or more substituents, and when there are multiple substituents at the substitutable site, the multiple substituents may be the same or different from each other. "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components. For example, physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0041] The excipients contained in the composition may be one or more buffers, stabilizers, anti-adherents, surfactants, wetting agents, lubricants, emulsifiers, binders, suspending agents, disintegrants, fillers, adsorbents, coatings (enteric or sustained-release), preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, aromas, flavoring agents and other known additives.

[0042] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to an organic or inorganic salt of a pharmaceutically acceptable compound.

[0043] When the compound is acidic or includes sufficiently acidic bioisosteres, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Such salts are derived from inorganic bases containing aluminum, ammonium, calcium, copper, iron, iron, lithium, magnesium, manganese salts, manganese, potassium, sodium, octane, etc. Specific embodiments include ammonium, calcium, magnesium, potassium and sodium salts. Salts are derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N.sup.1-dibenzylethylenediamine, ethylenediamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, meglumine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0044] When the compound is alkaline or includes a sufficiently alkaline bioisostere, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, sulfuric acid, succinic acid, tartaric acid, p-toluenesulfonic acid, etc. Specific embodiments include citric acid, hydrobromic acid, hydrochloric acid, phosphoric acid, sulfuric acid, maleic acid, tartaric acid, etc. Other exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, phosphate, acid phosphate, isonicotinic acid, lactic acid, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, fumarate, maleate, gentisinate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (e.g., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)).

[0045] In addition, the pharmaceutical preparation containing the compound can be a tablet, capsule, oral liquid, pill, granule, powder, ointment, patch, suppository, buccal tablet, eye drop, eye ointment, eye ointment, ear drop, spray, aerosol, inhalant, injection, etc.

[0046] The term "therapeutically effective amount" refers to the minimum amount of an effective compound or pharmaceutical agent necessary to ameliorate, cure or treat one or more symptoms of a disease or disorder.

[0047] In addition, the compounds and pharmaceutical compositions of the present invention can be administered alone or in combination with other medicaments. For combined treatment with more than one activating agent, when the activating agent is in a separate dosage formulation, the activating agent can be administered separately or in combination. In addition, the administration of one medicament can be carried out before, at the same time or after the administration of another medicament. When in combination with other medicaments, the "effective amount" of the second medicament will depend on the type of medicine used.

[0048] Route of administration

[0049] The one or more compounds of the present invention are administered by any route suitable for the patient to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), and parenteral (including subcutaneous, intramuscular), etc.

[0050] The compounds or pharmaceutical compositions of the present invention may also be included in a kit.

[0051] It should be noted that the reagents in the present invention without specifying their specific sources are conventional reagents purchased from the market.

[0052] The present invention will be further described below in conjunction with specific embodiments. These embodiments are only for the purpose of explanation and are not intended to limit the scope and essence of the present invention.

[0053] The experimental instruments and reagents used in the following examples are shown in Table 1 below.

[0054] Table 1

[0055]

[0056] Preparation Example

[0057] Preparation of limonin (hereinafter referred to as compound 1)

[0058] The Changshan pomelo peel is air-dried, then crushed into powder by a grinder, extracted with 95% ethanol for 4 times, the extracts are combined, concentrated under reduced pressure to obtain an ethanol crude extract, extracted with ethyl acetate until the supernatant is colorless, and concentrated under reduced pressure to obtain an ethyl acetate extract.

[0059] The ethyl acetate extract was subjected to silica gel column chromatography (200-300 mesh), and gradient elution was performed with an organic solvent of petroleum ether-ethyl acetate, and the eluate was collected; the collected elution components were further purified by gel column chromatography once and silica gel column chromatography once (300-400 mesh) to obtain limonin (compound 1).

[0060] Preparation of compound 1a:

[0061]

[0062] 50 mg of compound 1 was dissolved in 5 mL of dichloromethane, and then 50 mg of sodium cyanoborohydride (dissolved in 1 mL of anhydrous methanol) was added at 0°C, and the reaction solution was reacted for 24 hours. Dilute hydrochloric acid was added dropwise to the reaction solution to quench the reaction, and the pH was adjusted to 5, followed by extraction with dichloromethane (10 mL×3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:10) to obtain compound 1a (20 mg, 40%).

[0063] Preparation of compounds 1a, 1c-1g:

[0064] (1) 150 mg of compound 1 was dissolved in 15 mL of dichloromethane, and then 70 mg of sodium borohydride (dissolved in 2 mL of anhydrous methanol) was added at 0°C. After the reaction solution was reacted for 10 min, thin layer chromatography (TLC) was performed to detect that the raw material was basically consumed. 50 mL of the reaction solution was taken out, quenched with dilute hydrochloric acid, adjusted to pH ≈ 5, and concentrated under reduced pressure to remove dichloromethane. Then water (10 mL) was added and extracted with ethyl acetate (15 mL×3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:10) to obtain compound 1a (35 mg).

[0065] (2) After the remaining reaction solution was reacted for 20 min, TLC detected the formation of other products. 50 mL of the reaction solution was taken out, quenched with dilute hydrochloric acid, adjusted to pH ≈ 5, concentrated under reduced pressure to remove dichloromethane, then added with water (10 mL), and extracted with ethyl acetate (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:10) to obtain compounds 1c (12 mg) and 1d (9 mg).

[0066] (3) After the remaining reaction solution was reacted for 90 min, the reaction was quenched with dilute hydrochloric acid, the pH was adjusted to 5, and the dichloromethane was removed by concentration under reduced pressure. Water (10 mL) was then added and extracted with ethyl acetate (15 mL×3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:4) to obtain compounds 1e (8 mg), 1f (11 mg) and 1g (18 mg).

[0067] Preparation of compound 1h:

[0068]

[0069] 100 mg of compound 1 was dissolved in 10 mL of anhydrous tetrahydrofuran (THF), and then 0.5 mL of 1M lithium aluminum hydride tetrahydrofuran solution was added dropwise at 0°C. After the reaction solution was reacted for 1 hour, it was quenched with dilute hydrochloric acid, the pH was adjusted to 5, and the THF was removed by concentration under reduced pressure. Then water (15 mL) was added and extracted with ethyl acetate (20 mL×3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: methanol: dichloromethane = 1:10) to obtain compound 1h (55 mg, 55%).

[0070] Compound 1c: white powder. 1 H-NMR (400MHz, MeOD) δ7.40 (s, 1H), 7.35 (s, 1H), 6.35 (d, J = 0.87Hz, 1H), 5.3 1(d,J=1.97Hz,1H),4.97(s,1H),4.63(d,J=13.13Hz,1H),4.43(d,J=13.16I Hz,1H),4.63(s,1H),3.95(m,2H),2.86(d,J=16.35Hz,1H),2.76(dd,J=4.06,16.35Hz,1H),2.36(dd,J=2.86,12.48Hz,1 H), 1.99 (d, J=13.63Hz, 1H), 1.83 (m, 2H), 1.71 (m, 3H), 1.39 (m, 1H), 1.29 (s, 3H), 1.26 (s, 3H), 1.10 (s, 3H), 0.78 (s, 3H); 13C NMR (125MHz, MeOD) δ173.73, 143.44, 141.76, 124.83, 111.36, 89.07, 81.70, 81.04, 77.74, 73.77, 68.65, 67.71, 60 .09, 57.10, 48.28, 47.17, 46.34, 38.38, 36.93, 31.13, 30.59, 29.69, 21.91, 21.79, 19.82, 13.05.HRESI-MS: (M+H) + C 26 H 35 O 8 , calculated value 475.2326, measured value 475.2336.

[0071] Compound 1d. White powder. 1 H-NMR (400MHz, MeOD) δ7.39 (t, J=1.66Hz, 1H), 7.34 (d, J=0.67Hz, 1H), 6.33 (d, J=1.25Hz, 1H), 5.2 7 (d, J=1.62Hz, 1H), 5.03 (s, 1H), 4.62 (d, J=13.11Hz, 1H), 4.49 (d, J=13.10Hz, 1H), 4.06 (s, 1H), 3 .52 (t, J=2.47Hz, 1H), 3.48 (d, J=1.68Hz, 1H), 2.77 (m, 3H), 2.62 (dd, J=2.30, 13.63Hz, 1H), 1.92 ( m, 2H), 1.72 (m, 1H), 1.61 (m, 2H), 1.38 (m, 1H), 1.29 (s, 3H), 1.25 (s, 3H), 1.09 (s, 3H), 0.80 (s, 3H); 13 C NMR (125MHz, MeOD) δ173.82, 143.32, 141.88, 125.13, 111.49, 89.00, 82.19, 81.63, 73.94, 71.64, 69.01, 67.84, 60.84, 58 .33, 53.57, 47.23, 45.10, 43.48, 37.95, 36.97, 30.59, 28.13, 27.86, 21.91, 19.52, 18.84, 18.65, 18.36.HRESI-MS: (M+H) + C 26 H 35 O 8 Calculated value 475.2326, measured value 475.2335.

[0072] Compound 1e. White powder. 1H-NMR (400MHz, MeOD) δ7.37 (t, J=1.68Hz, 1H), 7.32 (m, 1H), 6.33 (d, J=1.19Hz, 1H), 5.30 (d, J=1.81Hz, 1H), 5 .01 (s, 1H), 4.01 (d, J = 13.55Hz, 1H), 3.90 (d, J = 13.10Hz, 1H), 3.72 (m, 1H), 3.63 (m, 2H), 3.57 (t, J = 2.74Hz, 2 H), 3.40 (d, J=1.84Hz, 1H), 2.56 (dd, J=4.11, 13.15Hz, 1H), 2.36 (m, 2H), 2.14 (m, 1H), 1.96 (m, 1H), 1.91 (m, 1 H), 1.85(m, 1H), 1.53(m, 1H), 1.45k(m, 1H), 1.30(s, 3H), 1.22(m, 1H), 1.19(s, 3H), 1.09(s, 3H), 0.97(s, 3H); 13 C NMR (125MHz, MeOD) δ143.16, 141.71, 125.34, 111.53, 89.09, 86.91, 79.40, 74.29, 72.98, 69.28, 62.88, 61.67, 59 .16, 54.96, 51.88, 46.08, 44.31, 37.65, 36.42, 30.46, 30.33, 28.66, 24.27, 21.49, 21.44, 18.46.HRESI-MS: (M+H) + C 26 H 39 O 8 Calculated value: 479.2639, measured value: 479.2644.

[0073] Compound 1f. White powder. 1H-NMR (400MHz, MeOD) δ7.39 (t, J=1.64Hz, 1H), 7.34 (s, 1H), 6.35 (d, J=1.18Hz, 1H), 5.34 (d, J=2.30Hz, 1H), 4.01 (m, 1H), 3.95 (m, 1H), 3.85 (m, 1H), 3.73 (m, 1H), 3.64 (m, 1H), 3.58 (m, 1H) ), 2.15 (m, 1H), 2.08 (d, J = 11.73Hz, 1H), 1.99 (m, 1H), 1.90 (m, 2H), 1.70 (m, 2H), 1.62 (m, 1H) , 1.28(m, 1H), 1.30(s, 3H), 1.22(m, 1H), 1.29(s, 3H), 1.19(s, 3H), 1.04(s, 3H), 0.97(s, 3H); 13 C NMR (125MHz, MeOD) δ143.33, 141.58, 124.97, 111.36, 89.03, 86.39, 79.03, 77.64, 73.80, 67.51, 62.50, 61.50, 61 .47, 55.59, 51.93, 49.22, 47.45, 38.24, 36.24, 34.35, 30.35, 29.97, 24.05, 23.53, 22.99, 12.10.HRESI-MS: (M+H) + C 26 H 39 O 8 Calculated value: 479.2639, measured value: 479.2628.

[0074] Compound 1g. White powder. 1 H-NMR (400MHz, MeOD) δ7.52 (s, 1H), 7.40 (t, J=1.62Hz, 1H), 6.53 (d, J=1.24Hz, 1H), 4.95 (s, 1H), 4 .08 (d, J=11.36Hz, 1H), 4.02 (d, J=5.27Hz, 2H), 3.80 (m, 1H), 3.79 (m, 1H), 3.76 (m, 1H), 3.72 (m, 1H) , 3.63(m, 1H), 3.60(m, 1H), 2.86(m, 1H), 2.13(m, 1H), 1.99(m, 1H), 1.93(m, 1H), 1.74(m, 1H), 1.65( m, 1H), 1.62 (m, 1H), 1.61 (m, 1H), 1.32 (m, 1H), 1.18 (s, 3H), 1.17 (s, 3H), 1.10 (s, 3H), 1.03 (s, 3H); 13C NMR (125MHz, MeOD) δ142.77, 142.56, 127.70, 112.29, 85.57, 79.77, 79.03, 78.46, 71.60, 66.67, 62.50, 62.08 , 61.65, 59.04, 51.30, 47.94, 45.70, 44.22, 36.07, 30.84, 27.37, 24.41, 23.81, 20.04, 15.42.HRESI-MS: (M+H) + C 26 H 41 O 8 Calculated value: 481.2796, measured value: 481.2806.

[0075] Compound 1h. White powder. 1 H-NMR (400MHz, MeOD) δ7.43 (m, 2H), 7.42 (d, J=0.92Hz, 1H), 5.81 (s, 1H), 4.3 2 (m, 1H), 4.07 (d, J = 11.10Hz, 1H), 3.91 (d, J = 11.05Hz, 2H), 3.74 (m, 2H), 3.6 0(m,2H),2.48(m,1H),2.17(m,2H),1.93(m,1H),1.67(s,3H),1.63(m,2H),1 .52(m, 1H), 1.32(m, 1H), 1.20(s, 3H), 1.07(s, 3H), 1.06(m, 1H), 1.03(s, 3H); 13 C NMR (125MHz, MeOD) δ143.45, 141.95, 128.15, 111.77, 86.55, 86.07, 78.79, 78.34, 72.62, 62.00, 61.71, 61.34, 59. 72, 52.07, 51.44, 50.88, 46.40, 38.39, 36.72, 34.88, 30.58, 27.08, 24.50, 23.85, 17.22, 14.18.HRESI-MS: (M+Na) + C 26 H 42 NaO 8 Calculated value 505.2772, measured value 505.2772.

[0076] Experimental Examples

[0077] In vitro anti-inflammatory activity screening test:

[0078] First, RAW264.7 macrophage cell line was selected for in vitro culture, and compound 1, compound 1a-1c and compound 1h (20 μM respectively) were selected to incubate the cells for 3 h, and then stimulated with 100 ng / mL lipopolysaccharide (LPS) for 2 h, the cell culture supernatant was extracted, and the expression level of tumor necrosis factor-α (TNF-α) in the supernatant was determined by ELISA. The results are shown in Table 2 below.

[0079] Table 2

[0080]

[0081]

[0082] As can be seen from Table 2, compounds 1a-1c and compound 1h have certain activity in inhibiting the increase of TNF-α produced by RAW264.7 macrophages and mouse primary microglia induced by LPS, and the activity is greatly improved compared with compound 1. This shows that the compounds obtained after reduction modification of limonin have definite anti-inflammatory activity and have the potential to be developed as anti-inflammatory drugs.

Claims

1. A limonin derivative or a pharmaceutically acceptable salt thereof, wherein: The limonin derivative is selected from one of the following compounds:

2. A method for preparing the limonin derivative according to claim 1, comprising the following steps: Preparation of compound 1c: 150 mg of limonin was dissolved in 15 mL of dichloromethane, and then 70 mg of sodium borohydride was added at 0°C. After the reaction solution was reacted for 10 min, thin layer chromatography (TLC) was performed to detect that the raw material was basically consumed. 50 mL of the reaction solution was taken out, quenched with dilute hydrochloric acid, adjusted to pH 5, and concentrated under reduced pressure to remove dichloromethane. Water was then added and extracted with ethyl acetate. After removing the organic phase, the remaining reaction solution was continued to react for 20 min. TLC detected that other products were generated. 50 mL of the reaction solution was taken out, quenched with dilute hydrochloric acid, adjusted to pH 5, and concentrated under reduced pressure to remove dichloromethane. Water was then added and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain compound 1c. Preparation of compound 1h: 100 mg of limonin was dissolved in 10 mL of anhydrous tetrahydrofuran, and then 0.5 mL of 1 M lithium aluminum hydride tetrahydrofuran solution was added dropwise at 0°C. After the reaction solution was reacted for 1 hour, it was quenched with dilute hydrochloric acid, the pH was adjusted to 5, and the THF was removed by concentration under reduced pressure. Water was then added and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain compound 1h.

3. A pharmaceutical composition comprising the limonin derivative or a pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable carrier.

4. The composition according to claim 3, wherein In the pharmaceutical composition, the mass percentage of the limonin derivative or the pharmaceutically acceptable salt thereof is 1wt% to 96wt%.

5. The composition according to claim 3, wherein In the pharmaceutical composition, the mass percentage of the limonin derivative or the pharmaceutically acceptable salt thereof is 10wt% to 85wt%.

6. The composition according to any one of claims 3 to 5, wherein The pharmaceutically acceptable carrier includes one or more selected from sugar, cellulose, gelatin, talc, solid lubricant, vegetable oil, polyol, emulsifier, wetting agent, colorant, flavoring agent, stabilizer, antioxidant, preservative and pyrogen-free water.

7. The composition according to claim 6, wherein The pharmaceutically acceptable carrier includes starch.

8. Use of the following limonin derivatives in the preparation of anti-inflammatory drugs:

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